Extended-Duration Dosing and Distribution of Dalbavancin into Bone and Articular Tissue
Antimicrob. Agents Chemother. April 2015 59:1849-1855
Michael W. Dunne, Sailaja Puttagunta, Craig R. Sprenger, Chris Rubino, Scott Van Wart, and James Baldassarre
aDurata Therapeutics, Inc., Branford, Connecticut, USA
bInstitute for Clinical Pharmacodynamics, Latham, New York, USA
cPRACS Institute, Ltd., Fargo, North Dakota, USA
Dalbavancin is an intravenous lipoglycopeptide with activity against Gram-positive pathogens and an MIC90 for Staphylococcus aureus of 0.06 μg/ml.
With a terminal half-life of >14 days, dosing regimens with infrequent parenteral administration become available to treat infectious diseases such as osteomyelitis and endocarditis that otherwise require daily dosing for many weeks.
In order to support a rationale for these novel regimens, the pharmacokinetics over an extended dosing interval and the distribution of dalbavancin into bone and articular tissue were studied in two phase I trials and pharmacokinetic modeling was performed.
Intravenous administration of 1,000 mg of dalbavancin on day 1 followed by 500 mg weekly for seven additional weeks was well tolerated and did not demonstrate evidence of drug accumulation.
In a separate study, dalbavancin concentrations in cortical bone 12 h after infusion of a single 1,000-mg intravenous infusion were 6.3 μg/g and 2 weeks later were 4.1 μg/g.
A two-dose, once-weekly regimen that would provide tissue exposure over the dalbavancin MIC for Staphylococcus aureus for 8 weeks, maximizing the initial exposure to treatment while minimizing the frequency of intravenous therapy, is proposed.